Genomic Instability in Human Pluripotent Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects
Genomic Instability in Human Pluripotent Stem Cells Arises from Replicative Stress and Chromosome Condensation Defects
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DOI：
10.1016/j.stem.2015.11.003
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发表时间：
2016-02-04
期刊：
影响因子：
23.9
通讯作者：
Kerem, Batsheva
中科院分区：
文献类型：
--
作者：
Lamm, Noa;Ben-David, Uri;Kerem, Batsheva
人多能干细胞（hPSC）在培养中经常获得染色体畸变，例如非整倍性。这些畸变随着时间的推移逐渐增加，并可能损害细胞的性质和临床用途。驱动初始基因组不稳定性及其持续进展的潜在机制在很大程度上是未知的。在这里，我们发现非整倍体hPSC经历DNA复制应激，导致有缺陷的染色体凝聚和分离。非整倍体hPSC显示出由转录因子SRF控制的肌动蛋白细胞骨架基因水平的改变，SRF的过表达可以挽救非整倍体hPSC中受损的染色体凝聚和分离缺陷。此外，二倍体hPSC中的SRF下调诱导复制应激和扰动凝聚，类似于非整倍体细胞中所见。总之，这些结果表明，SRF表达降低诱导复制应激和染色体凝聚缺陷，这是在非整倍体hPSC中观察到的持续染色体不稳定性的基础。类似的机制也可能在二倍体细胞不稳定性的起始期间起作用。
Human pluripotent stem cells (hPSCs) frequently acquire chromosomal aberrations such as aneuploidy in culture. These aberrations progressively increase over time and may compromise the properties and clinical utility of the cells. The underlying mechanisms that drive initial genomic instability and its continued progression are largely unknown. Here, we show that aneuploid hPSCs undergo DNA replication stress, resulting in defective chromosome condensation and segregation. Aneuploid hPSCs show altered levels of actin cytoskeletal genes controlled by the transcription factor SRF, and overexpression of SRF rescues impaired chromosome condensation and segregation defects in aneuploid hPSCs. Furthermore, SRF downregulation in diploid hPSCs induces replication stress and perturbed condensation similar to that seen in aneuploid cells. Together, these results suggest that decreased SRF expression induces replicative stress and chromosomal condensation defects that underlie the ongoing chromosomal instability seen in aneuploid hPSCs. A similar mechanism may also operate during initiation of instability in diploid cells.